ABSTRACT Eosinophilic esophagitis (EoE) is a recently characterized disease that has been rising dramatically over the past decade. It affects people of all ages with a preference in children and adults in their 30-40?s. EoE pathogenesis has been associated with allergen/immune reactions with characterized high levels of cytokines including IL-13. Prolonged inflammation results in tissue remodeling including hyperplasia of basal progenitor cells, subepithelial fibrosis and stricture of the esophagus. Although common topical corticosteroid therapy improves the clinicopathologic features in most patients, EoE almost always recurs when steroids are discontinued. Therefore, a better understanding of the pathobiology of this disease is necessitated for deriving novel effective treatment. We and others have previously shown that IL-13 plays a critical role in the initiation of EoE and subsequent tissue remodeling. However, the molecular mechanism by which IL-13 regulates basal progenitor cells remains largely unexplored. To address this issue we recently performed a comprehensive analysis of IL13-stimulated secretome, and identified that the 250kD isoform of Tenascin C (TNC250) is enriched in IL13-treated human esophageal basal cells, mouse and human EoE biopsies. Our preliminary data further show that knockdown of the transcripts encoding TNC250 leads to reduced proliferation of basal progenitor cells accompanied by decreased levels of TNFR-associated factors (TRAF)3 which is an E3 ubiquitin Ligase for MAP3K14 (also known as NF-kappa-B-inducing kinase (Nik)). Significantly, deletion of Nik leads to EoE with prominent basal cell hyperplasia and eosinophil infiltration. Our preliminary data further suggest that loss of Nik in the esophagus but not other tissues (e.g. thymus and hematopoietic system) is critical for EoE pathogenesis. Our hypothesis is that IL-13/TNC250 inhibits Nik-mediated non-canonical NF-?B signaling in the esophageal epithelium to promote EoE pathogenesis. We will test our hypothesis with the following specific aims: (Aim1) To test the hypothesis that TNC250 downstream of IL-13 promotes basal cell hyperplasia during EoE pathogenesis. (Aim2) To determine the role of Nik in EoE pathogenesis, which include two subaims: (Aim2a) To test the hypothesis that loss of Nik expression in the esophageal epithelium promotes EoE pathogenesis. (Aim2b) To test the hypothesis that loss of Nik promotes EoE through non-canonical NF-kB signaling. This project is expected to provide novel genetic and molecular mechanisms regulating basal progenitor cells. The insights gained through studying NF-kB signaling in EoE animal models will lay an important foundation for translating these findings into the clinic.